Retinoids, which regulate cell differentiation by modulating gene expression and are thus able to reverse the preneoplastic transformation of cells, have excellent potential as therapeutic agents for the treatment and prophylaxis of cancer. See, e.g.: A. B. Roberts et al., "Cellular Biology and Biochemistry of Retinoids," in The Retinoids, vol. 2, eds M. B. Sporn et al., Orlando: Academic Press, Inc., 1984, at pp. 209-286 (1984); and M. B. Sporn et al., "Biological Methods for Analysis and Assay of Retinoids," also in The Retinoids, vol. 2 (1984). Retinoids, particularly retinoic acid (RA) analogs, have been used in the treatment of leukemia, mycosis fungoides, basal cell carcinoma, and psoriasis and other hyperproliferative diseases of the skin (see R. C. Moon et al., "Retinoids and Cancer" in The Retinoids, vol. 2 (1984), supra). However, the systemic side effects of the compounds and their teratogenicity limit their utility. Side effects include, for example, bone remodeling, palmoplantar peeling, dermatitis, alopecia, hepatotoxicity, and systemic toxicity related as documented by H. Mayer et al., Experientia 34:1105 (1978) and by R. A. Pittsley et al., New Eng. J. Med. 308:1012 (1983).
The physiological activities of retinoids are mediated by two types of receptors, the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs). RARs as well as several related receptors require heterodimerization with RXRs for effective DNA binding and function. However, in the presence of 9-cis-retinoic acid, a ligand for both RARs and RXRs, RXRs can also form homodimers. Compounds that selectively activate RXR homodimers have not yet been defined.
The present invention provides a new class of retinoids in the form of bridged bicyclic aromatic compounds as will be described in detail herein. These new compounds are useful for regulating and/or eliciting selective gene expression by receptors in the retinoic acid family, i.e., RARs, RXRs, vitamin D receptors (VDRs), and thyroid hormone receptors (THRs). While not wishing to be bound by theory, it is postulated that the presently disclosed and claimed compounds are effective in modulating gene expression by virtue of their capability of interacting with a receptor protein that binds to the aforementioned receptors. The compounds are also believed to be useful in modulating gene expression by inducing formation of RXR homodimers in addition to RAR-RXR, VDR-RXR and THR-RXR heterodimers.
The novel compounds are thus useful for controlling cellular processes that are regulated by thyroid hormone, vitamin D, and retinoids such as 9-cis-retinoic acid, the natural ligand for RXR. Thus, acne, leukemia, psoriasis, and skin aging, all of which are regulated by retinoic acid, may be treated using the compounds of the invention, as may bone calcification, regulated by vitamin D, and energy levels, regulated by thyroid hormone. Unlike the synthetic retinoids of the prior art, the present compounds are believed to provide for substantially reduced side effects and teratogenicity.